The primary abnormalities leading to the development of essential hypertension remain unknown. This is due in part to the fact that the hypertensive phenotype can only be observed in vivo; proving that observed physiologic abnormalities are primary is difficult, if not impossible, from purely physiologic analysis. An alternative approach is to demonstrate that physiologic traits which may be causal to the development of hypertension are genetically transmitted. The genes responsible for such genetically determined phenotypes could then be mapped and ultimately identified, enabling demonstration of the primary genetic abnormalities that result in the observed physiologic phenotype. We have described related abnormalities in the renal blood flow and adrenal response to angiotensin II in 40% of patients with essential hypertension; we refer to such patients as non-modulators. We have proposed that these abnormalities contribute to the hypertension seen in affected individuals and have demonstrated that a number of predictions of this hypothesis are correct. Furthermore, we have presumptive evidence of the inheritance of this phenotype from several lines of evidence, including : 1) expression of the phenotype in normotensive offspring of hypertensives; 2) familial aggregation of the phenotype as both a dichotomous and quantitative trait; 3) association with a positive family history of hypertension; 4) bimodality of the phenotype within the general hypertensive population. These findings together suggest that non-modulation may show major gene inheritance. In this project we will define the genetics of non-modulation by pedigree analysis in hypertensive kindreds. We will analyze the results by complex segregation analysis to determine the contribution of major genes, polygenes and environmental influences on the expression of this phenotype. We anticipate finding evidence of major gene inheritance; such evidence will lead us to proceed with genetic mapping studies to identify the gene. As the defect in non-modulators appears to lie within the domain of the renin-angiotensin system, a number of candidate genes for linkage studies are evident.